Epileptiform activity reflects a depolarization which gives rise to a synchronous bursting of cortical neurons which is followed by a phase of hyperpolarization. The mechanism of this synchronous depolarization is not known, but its appearance in a variety of human seizure states and in most chemical, mechanical or electrical models of seizure in animals suggest a common underlying mechanism. Accumulating evidence suggests 1) a possible role of Ca++ currents in repetitive neuronal activity; and 2) the existence of at least 2-3 classes of Ca++ channels as defined by the affinity of several families of organic molecules: dihydropyridines (nimodipine), diphenylalkylamines (verapamil) and benzothiazephines (diltiazem). A direct test of the hypothesis that Ca++ plays a role in seizures is to determine whether putative organic Ca++ channel antagonists alter seizure activity. In recent survey studies, we have shown that nimodipine will suppress cortical epileptiform activity in the anesthetized rabbit and cat. To extend these preliminary observations, the present proposal will, in the halothane-anesthetized rabbit, examine in different seizure models the pharmacology of the site acted upon by nimodipine. The studies will specifically examine: 1) the dose dependency and relative activity of dihydropyridines (+) and (-) nimodipine, nifedepine, nicardipine, nitrendepine) diphenylalkylamines (demethoxyverapamil, (+) and (-) verapamil and D600), and benzothiazepines (diltiazem) in blocking ECS evoked epileptiform activity; 2) the relative activity of nimodipine, nitrendepine, verapamil and diltiazem in attenuating seizures generated in a variety of models of focal cerebral ischemia, topical bicuculline and systemic metrazol; 3) the interaction between diltiazem and verapamil with nimodipine; and 4) the ability of selected agents to penetrate the blood-brain barrier. These studies will therefore assess the possibility that specific receptor-associated Ca++ channels may indeed be directly associated with the repetitive bursting which characterizes different seizure states. These observations may suggest 1) certain Ca++ channel associated binding sites may reflect an essential role for certain subclasses of Ca++ channels, and 2) that such Ca++ channel antagonists represent a novel mode of anticonvulsant activity. Such observations would expand the clinical armamentarium currently available for this diversely evident clinical problem.